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l-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species

  • Applied genetics and molecular biotechnology
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Abstract

Tuberculosis caused by Mycobacterium tuberculosis remains a major global health concern; M. tuberculosis drug resistance and persistence further fueled the situation. Nutrient supportive therapy was intensively pursued to complement the conventional treatment, as well as their synergy with current antibiotics. To explore whether l-alanine can synergize with fluoroquinolones against M. tuberculosis, M. smegmatis was used as a surrogate in this study. We found that l-alanine can boost the bactericidal efficacy of fluoroquinolones, increasing the production of intracellular reactive oxygen species. This effect is very significant for persisters. Accelerated tricarboxylic acid cycle and/or nucleotide metabolism were observed after the addition of l-alanine. M. smegmatis MSMEG2660 is a homolog of the alanine dehydrogenase (Rv2780, MSMEG2659) negative regulator Rv2779c and involved in the l-alanine potentiation of fluoroquinolone via funneling more alanine into tricarboxylic acid. Deletion mutant of the MSMEG2660 (∆Ms2660) became more susceptible, and more readily revived from persistence. We firstly found that l-alanine can synergize with fluoroquinolones against Mycobacterium, especially the persisters via promoting metabolism. This will inspire new avenue to eliminate Mycobacterium persisters.

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Funding

This study was supported by National Natural Science Foundation (grant numbers 81871182, 81371851), National Key R&D Plan (2016YFC0502304), the Fundamental Research Funds for the Central Universities (grant numbers XDJK2017D101, XDJK2017D100, XDJK2017D099), and the Chongqing Municipal Education Commission for postgraduates innovation program, China (grant number CYB18076).

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Author notes

  1. Junfeng Zhen and Shuangquan Yan contributed equally to the work.

Authors and Affiliations

  1. Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Chongqing, China

    Junfeng Zhen, Shuangquan Yan, Yuzhu Li, Cao Ruan, Yue Li, Xue Li, Xiaokang Zhao, Xi Lv, Yan Ge, Ulrich Aymard Ekomi Moure & Jianping Xie

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  1. Junfeng Zhen
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  2. Shuangquan Yan
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  3. Yuzhu Li
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  5. Yue Li
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  9. Yan Ge
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Contributions

Jianping Xie and Shuangquan Yan directed the study; Junfeng Zhen, Shuangquan Yan, and Jianping Xie designed the study; Junfeng Zhen, Yuzhu Li, Cao Ruan, and Xiaokang Zhao performed the experiments; Yue Li, Xue Li, Xi Lv, and Yan Ge prepared the materials and analyzed the date. Junfeng Zhen, Jianping Xie, and Moure U.A.E. wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Jianping Xie.

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Zhen, J., Yan, S., Li, Y. et al. l-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species. Appl Microbiol Biotechnol 104, 2137–2147 (2020). https://doi.org/10.1007/s00253-020-10358-9

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